FAO Meeting Report No. PL/1965/10/1 WHO/Food Add./27.65 EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD The content of this document is the result of the deliberations of the Joint Meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues, which met in Rome, 15-22 March 19651 Food and Agriculture Organization of the United Nations World Health Organization 1965 1 Report of the second joint meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65 CHLORTHION Chemical name O,O-dimethyl-O-(3-chloro-4-nitrophenyl)-phosphorothioate; O,O-dimethyl-O-3-chloro-4-nitrophenyl phosphorothionate. Empirical formula C8H9O5NSCIP Structural formulaBIOLOGICAL DATA Biochemical aspects Chlorthion is activated to a potent cholinesterase inhibitor, chloroxon, in animals and plants. It is an active inhibitor of rat brain cholinesterase (DuBois et al., 1953). The molar I50 of chloroxon for human plasma cholinesterase (30 min. at 37°) in vitro is 4 × 10-7 (Fallscheer & Cook, 1956). Its in vivo mammalian toxicity is high in comparison with its low in vitro activity; this is ascribed to slow absorption from the peritoneal cavity, the gastro-intestinal tract and its slow passage into the central and peripheral nervous systems. However, when administered intraperitoneally in large doses (1000 mg/kg body-weight) it can gain access to and inhibit the cholinesterase activity of the brain. As it is the 3-chloro-derivative of "methyl parathion" it will probably be metabolized in a similar manner to the latter compound by oxidative replacement of the sulfur by oxygen to produce the active form of the insecticide. Such a metabolite does not appear to have been described and there are no reports in the literature to indicate whether the chloronitrophenyl residue is excreted as 3-chloro-4-nitrophenol, as would be expected by analogy with parathion. Few hydrolytic products have been found in rat urine after the administration of this compound (Plapp & Casida, 1958). There are no details of its metabolism in plants. Acute toxicity Animal Route LD50 mg/kg References body-weight Rat Oral 625-1 500 DuBois et al., 1953 Klimmer & Pfaff, 1955 Rat Intraperitoneal 750 DuBois et al., 1953 Mouse Oral 1 250 Klimmer & Pfaff, 1955 Guinea-pig Intraperitoneal 525 Klimmer & Pfaff, 1955 Differences in acute oral toxicity may be due to the purity of the material, in particular, the presence of more toxic oxidation products and of dimethyl-2-chloro-4-nitrophenyl thionophosphate. The vehicle used is also important. Combination of chlorthion with malathion and other phosphorothionates is said to result in a potentiation of its oral toxicity to mice (Rosenberg & Coon, 1958). Short-term studies Rat. Intraperitoneal injections of undiluted chlorthion to groups of 5 rats produced no mortality at a dose level of 50 mg/kg body-weight daily for 60 days; 100 mg/kg body-weight daily for 60 days resulted in 40% mortality. With 200 mg/kg body-weight daily all animals died within 5-10 days. The symptoms prior to death were similar to those observed for more toxic organo-phosphorus insecticides. Serum cholinesterase activity was decreased more than that of brain or submaxillary gland, probably owing to slow absorption into the tissues. At the lowest dose level (50 mg/kg body-weight daily) the serum cholinesterase activity fell to below 50% of normal after the first dose (DuBois et al., 1953). Rats (4 groups of 13 male and 4 groups of 13 female) fed for 120 days on diets containing 10, 20 and 50 ppm of chlorthion showed no significant change in growth rate, food consumption, or general appearance and no symptoms of cholinergic stimulation. Pathological examination showed no difference in the gross or microscopic features of the tissues compared with control animals. The animals fed at the 50 ppm level showed slight reduction in brain and submaxillary gland cholinesterase activity levels and a marked decrease in serum cholinesterase activity amounting to 76% inhibition. Reduction in serum cholinesterase activity was also noted at the 20 ppm level (61% inhibition) and at 10 ppm (27% inhibition). Reversal of the inhibition occurred within 2 weeks following removal of chlorthion from the diet (DuBois et al., 1956). Dog. Chlorthion fed to 4 dogs (2 male, 2 female) at dose levels of 0.5, 2, 5 and 15 ppm in the diet produced no depression of plasma and erythrocyte cholinesterase levels at 0.5, 2 and 5 ppm and gave only a questionable depression at 15 ppm over a period of 12 weeks (Williams et al., 1959). Long-term studies No data available. Comments on the experimental studies reported Although reliable acute toxicity data are available, no long-term toxicity tests on animals have been reported. No information is available about toxicity in man. EVALUATION Level causing no significant toxic effects in the rat and dog The data so far reported are not sufficient for an estimate to be made of an acceptable daily intake for man, especially as long-term studies are indicated because of the chemical nature of this compound. Further work required Chemical composition and toxicity of the residues. Observations on the effect in man. Long-term studies in rats including reproduction studies. REFERENCES DuBois, K. P., Doull, J., Deroin, J. & Cummings, O. K. (1953) Arch. industr. Hyg., 8, 350-8 DuBois, K. P., Doull, J. & Rehfuss, P. A. (1956) Report from Department of Pharmacology, University of Chicago Fallscheer, H. O. & Cook, J. W. (1956) J. Assoc. official Agr. Chem., 39, 691 Klimmer, O. R. & Pfaff, W. (1955) Arzneimitt-Forsch, 5 Plapp, P. W. & Casida, J. E. (1958) J. econ. Ent., 51, 800 Rosenberg, P. & Coon, J. M. (1958) Proc. Soc. exp. Biol. (N.Y.), 97, 836-9 Williams, M. W., Fuyat, H. N. & Fitzhugh, O. G. (1959) Toxicol. Appl. Pharmacol., 1, 1-7
See Also: Toxicological Abbreviations